Follow-up study of a patient with early onset cerebral amyloid angiopathy following childhood cadaveric dural graft.

We retrospectively studied the T2 star (T2*)-weighted magnetic resonance imaging (MRI) of a 40-year-old patient diagnosed with symptomatic early-onset cerebral amyloid angiopathy (CAA), occurring 34 years following childhood neurosurgery using a cadaveric dural patch. Our findings revealed that CAA associated with cadaveric dural transplantation could progress rapidly, sometimes with bilateral bleeding. This microbleed evolution is suggestive of water-soluble amyloid-ß transmission via cerebrospinal fluid alongside perivascular drainage pathways with deposition in the cerebral artery walls due to clearance disturbances. Multiple intracerebral hemorrhages associated with CAA with a childhood cadaveric dural graft should be considered a life-threatening medical complication.

Engineering advanced neural tissue constructs to mitigate acute cerebral inflammation after brain transplantation in rats.

Stroke, traumatic brain injuries, and other similar conditions often lead to significant loss of functional brain tissue and associated disruption of neuronal signaling. A common strategy for replacing lost neurons is the injection of dissociated neural stem cells or differentiated neurons. However, this method is unlikely to be suitable for replacing large brain cavities, and the resulting distribution of neurons may lack the necessary architecture to support appropriate brain function. Engineered neural tissues may be a viable alternative. Cell death is a prominent concern in neuronal grafting studies, a problem that could be magnified with the transplantation of engineered neural tissues. Here, we examined the effect of one contributor to cell death, acute cerebral inflammation, on neuronal survival after the transplantation of bioengineered constructs based on silk scaffolds. We found evidence of a high degree of inflammation and poor neuronal survival after introducing engineered constructs into the motor cortex of rats. Integrating a corticosteroid (methylprednisolone) into the constructs resulted in significantly improved neuron survival during the acute phase of inflammation. The improved construct survival was associated with decreased markers of inflammation and an anti-inflammatory state of the immune system due to the steroid treatment.

Dura mater graft-associated Creutzfeldt-Jakob disease with 30-year incubation period.

Over 60% of all patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) have been diagnosed in Japan. The incubation period has ranged from 1 to 30 years and the age at onset from 15 to 80 years. Here, we report a 77-year-old male Japanese autopsied dCJD case with the longest incubation period so far in Japan. He received a cadaveric dural graft at the right cranial convexity following a craniotomy for meningioma at the age of 46. At 30 years post-dural graft placement, disorientation was observed as an initial symptom of dCJD. He rapidly began to present with inconsistent speech, cognitive impairment and tremor of the left upper extremity. Occasional myoclonic jerks were predominantly observed on the left side. Brain MRI presented hyperintense signals on diffusion-weighted and T2-weighted images, at the right cerebral cortex. The most hyperintense lesion was located at the right parietal lobe, where the dura mater graft had been transplanted. Single-photon emission CT scan showed markedly decreased cerebral blood flow at the right parietal lobe. EEG revealed diffuse and slow activities with periodic sharp-wave complex discharges seen in the right parietal, temporal and occipital lobes. He died of pneumonia 9 months after onset. Brain pathology revealed non-plaque-type dCJD. Laterality of neuropathological changes, including spongiform change, neuronal loss, gliosis or PrP deposits, was not evident. Western blot analysis showed type 1 PrPCJD . Alzheimer-type pathology and PSP-like pathology were also observed.

Distinct origins of dura mater graft-associated Creutzfeldt-Jakob disease: past and future problems.

Dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) can be divided into two subgroups that exhibit distinct clinical and neuropathological features, with the majority represented by a non-plaque-type of dCJD (np-dCJD) and the minority by a plaque-type of dCJD (p-dCJD). The two distinct phenotypes of dCJD had been considered to be unrelated to the genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene or type (type 1 or type 2) of abnormal isoform of prion protein (PrPSc) in the brain, while these are major determinants of clinicopathological phenotypes of sporadic CJD (sCJD). The reason for the existence of two distinct subgroups in dCJD had remained elusive. Recent progress in research of the pathogenesis of dCJD has revealed that two distinct subgroups of dCJD are caused by infection with different PrPSc strains from sCJD, i.e., np-dCJD caused by infection with sCJD-MM1/MV1, and p-dCJD caused by infection with sCJD-VV2 or -MV2. These studies have also revealed previously unrecognized problems as follows: (i) the numbers of p-dCJD patients may increase in the future, (ii) the potential risks of secondary infection from dCJD, particularly from p-dCJD, may be considerable, and (iii) the effectiveness of the current PrPSc decontamination procedures against the PrPSc from p-dCJD is uncertain. To prevent secondary infection from p-dCJD, the establishment of effective decontamination procedures is an urgent issue. In this review, we summarize the past and future problems surrounding dCJD.

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

L-DOPA- and graft-induced dyskinesia following transplantation.

Recent clinical and preclinical data are shedding greater light on the nuances of transplantation of fetal tissue for the treatment of Parkinson's disease. The field was brought to a halt by the development of abnormal involuntary movements directly linked to the graft at the turn of the century. Since then, there has been further analysis of transplanted patients, the development of an animal model, and extensive preclinical experimentation to clarify the activity of the graft and examine closely its interactions with the host environment and the direct consequences for L-DOPA- and graft-induced dyskinesia. This review brings together the latest clinical and preclinical findings on the impact of transplantation on both L-DOPA- and graft-induced dyskinesia.

Current status of clinical trials of neural transplantation in Parkinson's disease.

There is a major unmet need for therapies for Parkinson's disease (PD) that go beyond treating symptoms and instead modify the course of the disease. The use of neural transplantation to repair the degenerating dopaminergic nigrostriatal pathway is one strategy by which this might be achieved. A series of small, independent open-label studies initially reported beneficial effects in patients treated with cell transplants derived from the fetal ventral mesencephalon. However, this initial promise was subsequently tempered by negative results from two larger, randomized studies, and the emergence of complications related to the procedure. The reason for these discordant results has been debated and this has led to the development of a new, multicenter, collaborative study--TRANSEURO--which will ultimately herald the next generation of clinical trials of cell therapy in PD, including those involving stem cells. In this chapter, we discuss what has been learned from previous studies of neural transplantation and go on to consider how relevant disease-modifying effects could be demonstrated in PD. We then go on to discuss how the design of future trials of transplantation-based therapies might be better conceived and executed.

Clinical translation of cell transplantation in the brain.

PURPOSE OF REVIEW: We identify the major recent advances in sourcing, preparation and delivery of primary and stem cell transplants into the brain, the preclinical studies in animal models and preliminary results on feasibility, safety and efficacy in an increasing range of human neurodegenerative diseases. RECENT FINDINGS: After a decade of debate concerning the reliability and safety of foetal cell transplantation in Parkinson's and Huntington's diseases, the conditions for eliminating side-effects and achieving more consistent efficacy are being implemented in renewed trials. In parallel, rapid advances are being made in identifying alternative sources of stem cells for transplantation, establishing the protocols for their reliable differentiation into specific neuronal phenotypes and translating these novel sources to cell therapy for patients in new clinical trials. Objective assessment of efficacy in patients does not always reveal outcomes that are as impressive as claimed - either in the preclinical animal models or by many commercial stem cell clinics - and even when stem cell therapies do appear to have been validated, the mechanisms are not always clear. SUMMARY: In spite of rapid progress, the conditions for reliable, well tolerated and effective cell therapies in brain disease are not yet fully established.

Clinical and experimental experiences of graft-induced dyskinesia.

Clinical trials evaluating transplantation of fetal tissue for the treatment of Parkinson's disease identified the unexpected side effect of abnormal movements in the 'off'l-DOPA state. Termed graft-induced dyskinesia (GID), various hypotheses have been put forward as to their cause but unfortunately the significant differences in clinical trial protocols and lack of a truly representative animal model has hindered the search for a conclusive basis for their appearance. Likely causative factors have been identified through careful examination of patient data and the use of amphetamine-induced dyskinesia in a rodent model of Parkinson's disease. New trials being planned in Europe hope to avoid GID, whilst maximizing on the functional benefit that can be afforded by this treatment approach but questions still remain as to the underlying mechanism.

Outcomes after endonasal septoplasty using caudal septal batten grafting.

BACKGROUND: This study evaluated surgical outcomes after endonasal septoplasty using caudal septal batten grafting for caudal septal deviation. METHODS: Fifty-six patients completed questionnaires to assess nasal obstruction by telephone interviews 8-63 months postoperatively (12.2 months on the average). In addition, patients assessed the severity of nasal symptoms (i.e., mouth breathing, mouth dryness, hyposmia, rhinorrhea, epistaxis, trouble sleeping, snoring, and being concerned about nasal problems) preoperatively and postoperatively using a visual analog scale (VAS). These VAS scores were compared with those of patients who underwent endonasal septoplasty using the cutting and suture technique. Complications were analyzed. RESULTS: Thirty-four (60.7%) patients reported their nasal obstruction was much improved, 17 (30.3%) reported their condition was improved, and 5 (8.9%) reported no change postoperatively. Patients reported a decrease in severity of all nasal symptoms (p < 0.05 for each). Their nasal obstruction improvement was not significantly different from that of patients managed by the cutting and suture technique. Complications after surgery included hyposmia in two cases, small septal perforation in one case, chondritis in one case, and septal abscess in one case, and all were managed successfully. No patient required revision septoplasty due to recurrence during the follow-up period. CONCLUSION: Endonasal septoplasty using caudal septal batten grafting for caudal septal deviation resulted in improvement in nasal obstruction and nasal symptoms and was associated with an acceptable complication rate.

Graft-induced dyskinesias in Parkinson's disease: High striatal serotonin/dopamine transporter ratio.

Graft-induced dyskinesias are a serious complication after neural transplantation in Parkinson's disease. One patient with Parkinson's disease, treated with fetal grafts 14 years ago and deep brain stimulation 6 years ago, showed marked improvement of motor symptoms but continued to suffer from OFF-medication graft-induced dyskinesias. The patient received a series of clinical and imaging assessments. Positron emission tomography and single-photon emission computed tomography 14 years posttransplantation revealed an elevated serotonin/dopamine transporter ratio in the grafted striatum compatible with serotonergic hyperinnervation. Inhibition of serotonin neuron activity by systemic administration of a 5-HT(1A) agonist suppressed graft-induced dyskinesias. Our data provide further evidence that serotonergic neurons mediate graft-induced dyskinesias in Parkinson's disease. Achieving a normal striatal serotonin/dopamine transporter ratio following transplantation of fetal tissue or stem cells should be necessary to avoid the development of graft-induced dyskinesias.

Human fetal neural precursor cells can up-regulate MHC class I and class II expression and elicit CD4 and CD8 T cell proliferation.

The use of allogeneic fetal neural precursor cells (NPCs) as a cell replacement therapy in neurodegenerative disorders holds great promise. However, previous studies concerning the possibility of alloimmune rejection of the transplanted cells have been inconclusive. Here, we used flow cytometry to quantify the expression of major histocompatibility complex (MHC) molecules by human NPCs, obtained from the cortex or ventral mesencephalon of fetuses with gestational ages between 7 and 11 weeks. MHC class I was undetectable on the surface of freshly isolated primary fetal tissue from either location, but increased over time in proliferating NPC cultures; after 7days in vitro, MHC class I was detectable on most cells. Following differentiation, MHC class I expression persisted on non-neuronal cells. MHC class II levels remained low at all time points but were inducible by pro-inflammatory cytokines, whereas the co-stimulatory molecules, CD80 and CD86, remained undetectable. Nonetheless, CD4+ and CD8+ T cells proliferated when peripheral blood mononuclear cells (PBMCs) were cultured with allogeneic NPCs. Weaker responses were obtained when NPCs were co-cultured with purified allogeneic responder T cells, suggesting that indirect allorecognition contributed significantly to PBMC responses. In conclusion, differentiating human NPCs are immunogenic in vitro, suggesting that they may trigger immune rejection unless transplant recipients are immunosuppressed.

Dyskinesias after neural transplantation in Parkinson's disease: what do we know and what is next?

Since the 1980 s, when cell transplantation into the brain as a cure for Parkinson's disease hit the headlines, several patients with Parkinson's disease have received transplantation of cells from aborted fetuses with the aim of replacing the dopamine cells destroyed by the disease. The results in human studies were unpredictable and raised controversy. Some patients showed remarkable improvement, but many of the patients who underwent transplantation experienced serious disabling adverse reactions, putting an end to human trials since the late 1990 s. These side effects consisted of patients' developing troublesome involuntary, uncontrolled movements in the absence of dopaminergic medication, so-called off-phase, graft-induced dyskinesias. Notwithstanding the several mechanisms having been proposed, the pathogenesis of this type of dyskinesias remained unclear and there was no effective treatment. It has been suggested that graft-induced dyskinesias could be related to fiber outgrowth from the graft causing increased dopamine release, that could be related to the failure of grafts to restore a precise distribution of dopaminergic synaptic contacts on host neurons or may also be induced by inflammatory and immune responses around the graft. A recent study, however, hypothesized that an important factor for the development of graft-induced dyskinesias could include the composition of the cell suspension and specifically that a high proportion of serotonergic neurons cografted in these transplants engage in nonphysiological properties such as false transmitter release. The findings from this study showed serotonergic hyperinnervation in the grafted striatum of two patients with Parkinson's disease who exhibited major motor recovery after transplantation with fetal mesencephalic tissue but later developed graft-induced dyskinesias. Moreover, the dyskinesias were significantly attenuated by administration of a serotonin agonist, which activates the inhibitory serotonin autoreceptors and attenuates transmitter release from serotonergic neurons, indicating that graft-induced dyskinesias were caused by the dense serotonergic innervation engaging in false transmitter release. Here the implications of the recent findings for the development of new human trials testing the safety and efficacy of cell transplantation in patients with Parkinson's disease are discussed.

Brain imaging after neural transplantation.

Functional imaging has provided objective evidence that human fetal ventral mesencephalic tissue implanted in the striatum of Parkinson's disease patients can survive, grow, release dopamine, normalize brain metabolism, and restore striatal-cortical connections. Open-label clinical trials have shown robust clinical improvement in several PD patients but these results were not replicated in two double-blind sham-surgery controlled clinical trials. Graft-induced dyskinesias are serious adverse effects and a major roadblock for the further development of cell therapies, and functional imaging can help investigate the mechanisms underlying their cause. Functional imaging can also aid future trials by improving patient selection, assessing restoration of brain connectivity, and monitor inflammatory processes. Although functional imaging cannot currently be used as a primary endpoint in clinical transplantation trials, it can provide additional valuable information alongside clinical observations.

Neural grafting in Parkinson's disease Problems and possibilities.

Neural transplantation has emerged as a possible therapy for Parkinson's disease (PD). Clinical studies performed during the 1990s, where dopaminergic neurons derived from the human embryonic brain were transplanted into striatum of patients with PD, provided proof-of-principle that long-lasting therapeutic benefits can be achieved. Subsequent studies, in particular two that followed a double-blind, sham surgery, placebo-control design, showed variable and mostly negative results. They also revealed that some patients develop involuntary movements, so called graft-induced dyskinesias, as side effects. Thus, while nigral transplants clearly work well in select PD cases, the technique needs refinement before it can successfully be performed in a large series of patients. In this review, we describe the clinical neural transplantation trials in PD and the likely importance of factors such as patient selection, trial design, preparation of the donor tissue, and surgical techniques for successful outcome and avoiding unwanted side effects. We also highlight that it was recently found that neuropathological signs typical for PD can appear inside some of the grafted neurons over a decade after surgery. Finally, we discuss future possibilities offered by stem cells as potential sources of dopamine neurons that can be used for transplantation in PD.

Neural grafting in Parkinson's disease unraveling the mechanisms underlying graft-induced dyskinesia.

The development of neural transplantation as a treatment for Parkinson's disease has been compromised by a lack of functional efficacy and the appearance of transplant-induced motor side-effects in some patients. Since the first reports of these graft-induced dyskinesias (GID), and the realization of their impact on the progress of the field, a great deal of experimental work has been performed to determine the underlying cause(s) of this problematic side-effect. In this review we describe the clinical phenomenon of GID, explore the different representations of GID in rodent models, and examine the various hypotheses that have been postulated to be the cause. Based on the available clinical and preclinical data we outline strategies to avoid GID in future clinical trials using fetal cell transplants or cell preparations derived from stem cells.

Graft-induced dyskinesias in Parkinson's disease: what is it all about?

The treatment of Parkinson's disease with grafts of fetal ventral mesencephalic tissue has shown some success, but can result in graft-induced dyskinesias (GIDs). Recently in Science Translational Medicine, Politis et al. (2010) demonstrate that GIDs may originate from serotoninergic neurons that are cografted in these transplants.